Novel azole-urea hybrids as VEGFR-2 inhibitors: Synthesis, in vitro antiproliferative evaluation and in silico studies

dc.authorscopusid58622062100
dc.authorscopusid57190582389
dc.authorscopusid57208031609
dc.authorscopusid24400636500
dc.authorscopusid58396726400
dc.authorscopusid6506158277
dc.authorscopusid26638740000
dc.contributor.authorYelekçi, Kemal
dc.contributor.authorKulabaş, N.
dc.contributor.authorErdoğan, Ö.
dc.contributor.authorÇevik, Ö.
dc.contributor.authorDere, D.
dc.contributor.authorYelekçi, K.
dc.contributor.authorDanış, Ö.
dc.date.accessioned2023-10-19T15:05:13Z
dc.date.available2023-10-19T15:05:13Z
dc.date.issued2023
dc.department-tempShirzad, M.M., Department of Chemistry, Faculty of Science, Marmara University, İstanbul, 34722, Turkey; Kulabaş, N., Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Marmara University, İstanbul, 34854, Turkey; Erdoğan, Ö., Department of Medical Biochemistry, Medical Faculty, Gaziantep Islam Science and Technology, Gaziantep, 27010, Turkey; Çevik, Ö., Department of Biochemistry, Faculty of Medicine, Adnan Menderes University, Aydın, 09010, Turkey; Dere, D., Department of Bioinformatics and Genetics, Faculty of Engineering and Natural Sciences, Kadir Has University, İstanbul, Turkey; Yelekçi, K., Department of Bioinformatics and Genetics, Faculty of Engineering and Natural Sciences, Kadir Has University, İstanbul, Turkey; Danış, Ö., Department of Chemistry, Faculty of Science, Marmara University, İstanbul, 34722, Turkey; Küçükgüzel, İ., Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Fenerbahçe University, İstanbul, 34758, Turkeyen_US
dc.description.abstractThe vascular endothelial growth factor receptor-2 (VEGFR-2) is a receptor tyrosine kinase known to be abnormally expressed in various malignant tumors, including breast cancer, and is considered one of the most important contributors to tumor angiogenesis. Sorafenib is one of many VEGFR-2 inhibitors that have received approval for clinical use from the US FDA in recent years. Accordingly, in this study, the synthesis of two new pyrazoles, six 1,3,4-oxadiazoles, four 1,3,4-thiadiazoles, and ten 1,2,4-triazole-3-thione derivatives having structural characteristics similar to sorafenib was carried out. A preliminary screening of synthesized compounds and known inhibitors sorafenib and staurosporine at 10 µM concentration on in vitro activity of VEGFR-2 was performed, and compounds 10c, 8a, and 11 g were identified as the most potent derivatives with% VEGFR-2 residual activities lower than 30%, and dose-dependent inhibition studies was carried out to determine the IC50 values of these inhibitors. Compound 10c was found to be the most potent inhibitor of VEGFR-2 activity with an IC50 value of 0.664 µM. The anti-proliferative activity of synthesized derivatives was assessed against a breast carcinoma (MCF-7) cell line, a triple negative human breast adenocarcinoma (MDA-MB-231) cell line, and noncancerous fibroblast cells (L929). Compound 8a displayed superior activity when compared to sorafenib against MCF-7 (7.69 fold) and MDA-MB-231 (1.52 fold) cell lines while displaying 3.75-fold less toxicity against the normal L929 cell line. Annexin V binding assay revealed that compound 8a significantly increased early and late apoptosis in MCF-7 cells and late apoptosis and necrosis in MDA-MB-231 cells. Computational studies such as molecular docking and ADMET evaluation were performed to elucidate the binding interactions and drug-likeness of the synthesized compounds. The results indicate that compound 8a could be a promising candidate for the development of a novel anti-angiogenic and anti-proliferative agent. © 2023en_US
dc.description.sponsorshipMarmara Üniversitesi: FENC-DRP-170419-0127en_US
dc.description.sponsorshipThis work was supported by Marmara University Scientific Research Fund, Türkiye through Project FENC-DRP-170419-0127.en_US
dc.identifier.citation0
dc.identifier.doi10.1016/j.molstruc.2023.136448en_US
dc.identifier.issn0022-2860
dc.identifier.scopus2-s2.0-85172449865en_US
dc.identifier.scopusqualityQ2
dc.identifier.urihttps://doi.org/10.1016/j.molstruc.2023.136448
dc.identifier.urihttps://hdl.handle.net/20.500.12469/4745
dc.identifier.volume1294en_US
dc.identifier.wosqualityN/A
dc.khas20231019-Scopusen_US
dc.language.isoenen_US
dc.publisherElsevier B.V.en_US
dc.relation.ispartofJournal of Molecular Structureen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/closedAccessen_US
dc.subject1,2,4-triazole-3-thioneen_US
dc.subject1,3,4-oxadiazolesen_US
dc.subject1,3,4-thiadiazolesen_US
dc.subjectAnti-canceren_US
dc.subjectPyrazoleen_US
dc.subjectVEGFR-2 inhibitoren_US
dc.subjectAmino acidsen_US
dc.subjectBinding energyen_US
dc.subjectCell cultureen_US
dc.subjectDiagnosisen_US
dc.subjectDiseasesen_US
dc.subjectTumorsen_US
dc.subjectUreaen_US
dc.subject1,2,4-triazole-3-thioneen_US
dc.subject1,3,4-oxadiazoleen_US
dc.subject1,3,4-thiadiazoleen_US
dc.subjectAnti-canceren_US
dc.subjectOxadiazolesen_US
dc.subjectPyrazolesen_US
dc.subjectThiadiazolesen_US
dc.subjectThionesen_US
dc.subjectVascular endothelial growth factor receptoren_US
dc.subjectVascular endothelial growth factor receptor-2 inhibitoren_US
dc.subjectCell deathen_US
dc.titleNovel azole-urea hybrids as VEGFR-2 inhibitors: Synthesis, in vitro antiproliferative evaluation and in silico studiesen_US
dc.typeArticleen_US
dspace.entity.typePublication
relation.isAuthorOfPublication9407938e-3d31-453b-9199-aaa8280a66c5
relation.isAuthorOfPublication.latestForDiscovery9407938e-3d31-453b-9199-aaa8280a66c5

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